Orexin is a neurotransmitter that regulates wakefulness and appetite. Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hypeiprolactinemia; hypophysis tumour/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general and other diseases related to general orexin system dysfunction.
Some orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions, in particular they are capable of promoting sleep in animals and humans are described in the art. One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which has the structure according to Formula I
and which is e.g. described in US 20080132490 A1, WO 2008/069997 and Cox et al (2010) Journal of Medicinal Chemistry, 53 (14): 5320-5332. Alternative names for this compound are 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-thiazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzobenzoxazol and [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone.
The synthesis of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (hereinunder and above referred to as “Suvorexant” or “orexin receptor antagonist”) is described in WO 2008/069997. According to WO 2008/069997 (Example 3) the compound is finally obtained as a white solid. As may be taken from the examples presented hereinunder, this solid is either the crystalline form I or the crystalline form II depending on the crystallization temperature employed. No amorphous form of suvorexant is described in WO 2008/069997.
The crystalline forms I and II of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone are further explicitly described in WO 2012/148553 A1. There it is stated that forms I and II are enantiotropically related with a transition temperature of 35-40° C. Moreover, a pharmaceutical composition comprising a crystalline form of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone is described. However, the crystalline forms of suvorexant only show limited solubility and bioavailability.
Thus, WO 2013/181174 proposes compositions comprising suvorexant together with a concentration enhancing polymer, which form together an amorphous dispersion. The composition however only comprises about 4% to 40% suvorexant.
Thus, there is still there is still the need for advantageous compositions comprising a high amount of suvorexant which show a high solubility and/or bioavailability and a long-term stability.
Therefore, it was an object of the present invention to provide compositions comprising suvorexant, which compositions have advantageous characteristics regarding solubility and/or bioavailability and/or the stability.